Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Abstract

The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARα) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3β (GSK3β) activity that, through phosphorylation, stabilizes and increases the level of the RevErbα protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARα-RevErbα axis in muscle and heart and accounts for the retarded shift of their PCCs.shifted eating | shifted peripheral circadian clocks | metabolic alterations | RevErbα | PPARα P ioneering studies (1, 2) have established that switching the feeding time in mice from the "active" phase [dark period of the light-dark (L/D) cycle] to the "rest" phase (light period), i.e., restricted feeding (RF), overrides the suprachiasmatic nucleus (SCN) circadian clock (CC)-derived signals and acts as a "zeitgeber" for peripheral CCs (PCCs), leading to a 12-h shift in the time at which components of PCCs are expressed. Numerous studies have shown that under homeostatic conditions, the functions of PCCs and metabolism are tightly linked and that perturbations in their interactions leads to pathologies, e.g., obesity and metabolic syndrome (3-5).The identity of some of the molecular pathways that couple PCCs to metabolism are known (3-5), but it is largely unknown how environmental cues, e.g., altered feeding schedules, may directly perturb the expression of individual CC components (5-7), thereby leading to obesity and a metabolic syndrome-like pathology (5). Assuming that specific metabolic perturbations generated by switching the feeding time could selectively affect the time of expression of some of the CC core components, we looked for both metabolic and PCC alterations at early RF times. We report here a comprehensive temporal analysis, an...

Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome

“…S1 C and D and In RF Mice, the Expression of PCC-Controlled Output Genes Is Shifted by 12 h with Respect to the Diurnal Active and Rest Phases Controlled by the Central SCN CC), we explored the molecular basis of its maintenance and found that the active phase RF hypoinsulinemia is a recurring event during long-term RF regime ( Fig. 1A and In RF Mice, the Expression of PCC-Controlled Output Genes Is Shifted by 12 h with Respect to the Diurnal Active and Rest Phases Controlled by the Central SCN CC), which, as expected (5,11), leads to an increase in GSK3β-mediated phosphorylated RevErbα (pRevErbα) level at "Zeitgeber" (ZT) 0 ( Fig. 1 E and F and Fig.…”

“…We recently elucidated (5) how the RF-induced decrease in insulin (INS) blood level during the active phase triggers an aberrant activation of nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα) through phosphorylation by active glycogen synthase kinase 3β (GSK3β; Fig. 1F) (5). This RevErbα phosphorylation prevents its proteasome degradation (10) and is crucial for the repression of RORα/RevErbα response element (RORE)-DNA binding sequence (DBS)-containing genes (e.g., Bmal1, Cry1), which is a critical event in the initiation of the RF-induced shift of PCCs (5).…”

“…1F) (5). This RevErbα phosphorylation prevents its proteasome degradation (10) and is crucial for the repression of RORα/RevErbα response element (RORE)-DNA binding sequence (DBS)-containing genes (e.g., Bmal1, Cry1), which is a critical event in the initiation of the RF-induced shift of PCCs (5).…”

“…However, the molecular mechanisms that confer to the SCN CC an insensitivity to RF, as well as the consequences of the misalignment between the PCCs and the master SCN CC on homeostasis, are still largely unexplored (3,6). In the present study, we elucidated, at the molecular level, how the SCN CC is protected against the RF-induced shift of PCCs, which is induced by metabolic alterations (5), and how the misalignment between the master SCN CC and the PCCs generates a metabolic syndrome-like pathology, similar to that exhibited by shift workers (3, 6-9).…”

“…As the SCN CC is not affected during RF (4), this situation leads to a misalignment between the diurnal active and rest phases and the expression of PCC components. We recently unveiled in mice the origin and the identity of the molecular signals through which RF leads to this 12-h shift in the expression of PCC components (5). However, the molecular mechanisms that confer to the SCN CC an insensitivity to RF, as well as the consequences of the misalignment between the PCCs and the master SCN CC on homeostasis, are still largely unexplored (3,6).…”